6JED

Crystal structure of IMP-1 metallo-beta-lactamase in a complex with MCR

6JED の概要

• エントリーDOI: 10.2210/pdb6jed/pdb
• 分子名称: Metallo-beta-lactamase type 2, ZINC ION, SULFANYLACETIC ACID, ... (5 entities in total)
• 機能のキーワード: metallo-beta-lactamase, hydrolase
• 由来する生物種: Serratia marcescens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25607.92

構造登録者

Wachino, J. (登録日: 2019-02-05, 公開日: 2019-08-07, 最終更新日: 2023-11-22)

主引用文献

Wachino, J.,Kanechi, R.,Nishino, E.,Mochizuki, M.,Jin, W.,Kimura, K.,Kurosaki, H.,Arakawa, Y.
4-Amino-2-Sulfanylbenzoic Acid as a Potent Subclass B3 Metallo-beta-Lactamase-Specific Inhibitor Applicable for Distinguishing Metallo-beta-Lactamase Subclasses.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: The number of cases of infection with carbapenem-resistant (CRE) has been increasing and has become a major clinical and public health concern. Production of metallo-β-lactamases (MBLs) is one of the principal carbapenem resistance mechanisms in CRE. Therefore, developing MBL inhibitors is a promising strategy to overcome the problems of carbapenem resistance conferred by MBLs. To date, the development and evaluation of MBL inhibitors have focused on subclass B1 MBLs but not on B3 MBLs. In the present study, we searched for B3 MBL (specifically, SMB-1) inhibitors and found thiosalicylic acid (TSA) to be a potent inhibitor of B3 SMB-1 MBL (50% inhibitory concentration [IC], 0.95 μM). TSA inhibited the purified SMB-1 to a considerable degree but was not active against cells producing SMB-1, as the meropenem (MEM) MIC for the SMB-1 producer was only slightly reduced with TSA. We then introduced a primary amine to TSA and synthesized 4-amino-2-sulfanylbenzoic acid (ASB), which substantially reduced the MEM MICs for SMB-1 producers. X-ray crystallographic analyses revealed that ASB binds to the two zinc ions, Ser221, and Thr223 at the active site of SMB-1. These are ubiquitously conserved residues across clinically relevant B3 MBLs. ASB also significantly inhibited other B3 MBLs, including AIM-1, LMB-1, and L1. Therefore, the characterization of ASB provides a starting point for the development of optimum B3 MBL inhibitors.

PubMed: 31405855
DOI: 10.1128/AAC.01197-19

実験手法

X-RAY DIFFRACTION (1.57 Å)